Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Department of Pharmacology, University of the Basque Country UPV/EHU, E-48940 Leioa, Bizkaia, Spain.Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), University of the Basque Country UPV/EHU, E-48940 Leioa, Bizkaia, Spain.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.Department of Pharmacology, University of the Basque Country UPV/EHU, E-48940 Leioa, Bizkaia, Spain.Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), University of the Basque Country UPV/EHU, E-48940 Leioa, Bizkaia, Spain.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Via AAAS ID

This article is available to AAAS members. If you are a AAAS Member use your via AAAS ID and password to log in. Not a member? Click here to join.

Via your Institution

Log in through your institution

If your organization uses OpenAthens, you can log in using your OpenAthens username and password. To check if your institution is supported, please see this list. Contact your library for more details.

Log in through your institution

You may be able to gain access using your login credentials for your institution. Contact your library if you do not have a username and password.

Free with registration

Science Signaling research is available free with registration one year after its publication. To get your free access please visit our registration form.

One to bind, one to signal

In addition to forming homodimers and heterodimers, G protein–coupled receptors (GPCRs) can form multiprotein complexes (heteromers) with other GPCRs. For example, the metabotropic glutamate receptor mGlu2, which couples to Gi/o proteins, and the 5-HT2A serotonin receptor, which couples to Gq/11, form heteromeric complexes. Moreno et al. performed a structure-function analysis to determine the signaling properties of these heteromers. Stimulation of cells expressing mGlu2–5-HT2A heteromers with an mGlu2 agonist led to Gq/11-dependent signaling by 5-HT2A, a response lacking in cells from 5-HT2A–deficient mice. Furthermore, the analysis of postmortem brains of schizophrenia patients indicated less mGlu2-dependent Gq/11 signaling compared to that in normal brains, suggesting that these heteromeric complexes may be dysregulated in disease.

Abstract

Heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors (GPCRs) can form multiprotein complexes (heteromers), which can alter the pharmacology and functions of the constituent receptors. Previous findings demonstrated that the Gq/11-coupled serotonin 5-HT2A receptor and the Gi/o-coupled metabotropic glutamate 2 (mGlu2) receptor—GPCRs that are involved in signaling alterations associated with psychosis—assemble into a heteromeric complex in the mammalian brain. In single-cell experiments with various mutant versions of the mGlu2 receptor, we showed that stimulation of cells expressing mGlu2–5-HT2A heteromers with an mGlu2 agonist led to activation of Gq/11 proteins by the 5-HT2A receptors. For this crosstalk to occur, one of the mGlu2 subunits had to couple to Gi/o proteins, and we determined the relative location of the Gi/o-contacting subunit within the mGlu2 homodimer of the heteromeric complex. Additionally, mGlu2-dependent activation of Gq/11, but not Gi/o, was reduced in the frontal cortex of 5-HT2A knockout mice and was reduced in the frontal cortex of postmortem brains from schizophrenic patients. These findings offer structural insights into this important target in molecular psychiatry.